Zinc finger-like protein that regulates apoptosis (Zfra) is a naturally-occurring small peptide consisting of 31 amino acid residues. Zfra regulates tumor necrosis factor (TNF)-mediated cell death by binding to and inhibiting proteins involved in the TNF signaling pathway, including tumor suppressor WWOX (through the first WW domain and ADH/SDR domain), TNF receptor- or Fas-associated death domain proteins (TRADD and FADD), and receptor-interacting protein (RIP). Hong, et al., 2007, BMC Mol Biol, 8, 50. Moreover, Zfra sequesters cJun N-terminal kinase 1 (JNK1), p53, WWOX, nuclear factor NF-κB and phosphor-ERK in the cytoplasm. Hong et al., 2007; and Hsu et al., 2005, Biochem Biophys Res Commun, 327, 415-23.
Zfra may also participate in cell death regulation via the mitochondrial pathway. Dudekula et al., 2010, Aging (Albany N.Y.), 2, 1023-9; and Hsu et al., (2008) Cell Signal, 20, 1303-12. Overexpression of Zfra induced cell death, while the S8G-Zfra mutant could not induce cell death, suggesting that Serb phosphorylation is essential for Zfra translocation to the mitochondria, and is important for Zfra-induced cell death. Zfra blocks WOX1-induced cytochrome c release from the mitochondria, and induces apoptosis through dissipation of mitochondrial membrane potential (MMP), indicating a novel death regulation in mitochondria pathway. Dudekula et al., 2010; and Hsu et al., 2008.